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The Journal of Immunology, 2002, 169: 2828-2831.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Profound Defect in T Cell Responses in TNF Receptor-Associated Factor 2 Dominant Negative Mice1

Jennifer L. Cannons2, Edward M. Bertram and Tania H. Watts3

Department of Immunology, University of Toronto, Toronto, Ontario, Canada


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
TNFR-associated factor 2 (TRAF2) is an adapter protein that links several members of the TNFR family to downstream signaling pathways. Mice expressing a dominant negative form of TRAF2 in their lymphoid cells (TRAF2.DN mice) have a profound defect in T cell responses to allogeneic APC. In contrast, APC from wild-type or TRAF2.DN mice show an equivalent level of stimulation in a MLR. Ab production and class switch are unimpaired in TRAF2.DN mice. Thus, defects in the TRAF.DN mice appear to be limited to T cells. TRAF2.DN mice demonstrate an impaired T cell response to influenza virus, including decreased secondary expansion of IFN-{gamma}-secreting T cells as well as a decrease in CTL activity. CD4 T cell production of IL-2 was also dramatically impaired in TRAF2.DN mice. These studies suggest an essential role of TRAF2-linked receptors in secondary CD4 and CD8 T cell responses and have important implications for transplantation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Members of the TNFR family are important regulators of lymphocyte life and death. Signaling via TNFR family members follows two main paradigms: death domain-containing receptors such as TNFR1, Fas, and death receptor 4 initially recruit signaling molecules via death domain-death domain interactions, whereas members of the TNFR family that lack death domains, such as TNFRII, CD40, 4-1BB, OX40, and CD27, initiate their signal transduction cascades by recruiting TNFR-associated factors (TRAFs)4 (1, 2). The six TRAF family members have in common a conserved C-terminal TRAF domain, responsible for interactions with cytoplasmic tails of membrane receptors as well as homo- or hetero-oligomerization of TRAF proteins (1). The N-terminal domains of TRAF2–TRAF6 contain zinc and RING fingers, thought to be responsible for their downstream functions. Truncation of the N-terminal RING fingers of TRAF proteins converts them to dominant negative mutants (3).

TRAF2 was first identified biochemically as part of the TNFRII signaling complex (4). Overexpression of TRAF2 activates NF-{kappa}{beta} and AP-1 (3). TRAF2 binds directly to the cytoplasmic tails of several TNFR family members, including TNFRII, CD40, OX40, 4-1BB, CD30, CD27, and latent membrane protein-1 (1). TRAF2, via its C-terminal TRAF domain, binds to conserved five- to seven-residue motifs enriched in acidic amino acids (1, 5). In addition to its direct binding to a number of TNFR family members, TRAF2 is also recruited to the signaling complexes of death domain-containing TNFR family members and can act as a link to apoptotic pathways as well as providing links to NF-{kappa}B and cell survival (1, 2). Analysis of T cells from TRAF2-/- or TRAF2.DN mice demonstrated that TRAF2 is essential for c-Jun N-terminal kinase (JNK) activation in response to TNF or CD40 ligand (CD40L) but is dispensable for NF-{kappa}B activation (6, 7). Embryonic fibroblasts from mice deficient in both TRAF2 and TRAF5 show significant impairment of NF-{kappa}B nuclear translocation. Thus, there is redundancy of TRAF2 and TRAF5 function with respect to NF-{kappa}Bactivation in some cell types (8). TRAF2 is also essential for TNF-related activation-induced cytokine (TRANCE) and 4-1BBL-mediated signal transduction (9, 10, 11). Overexpression of a TRAF2.DN protein can block NF-{kappa}B activation in response to TRANCE as well as JNK and p38 activation and IL-2 production in response to 4-1BBL (9, 10, 11).

TRAF2-/- mice exhibit perinatal lethality (7) that can be overcome by crossing the mice onto a TNFRI or TNF-deficient background. The TNF-/-TRAF2-/- or TNFRI-/-TRAF2-/- mice exhibit reduced NF-{kappa}B activation in response to CD40 signaling and defective neutralizing Ab response to vesicular stomatitis virus (12).

TRAF2.DN mice exhibit splenomegaly and lymphadenopathy, largely due to an enlarged B cell compartment (6). B cells from TRAF2.DN mice have normal responses to anti-IgM but slightly enhanced responses to LPS and CD40L. In contrast, T cells from TRAF2.DN mice have a decreased ability to proliferate to immobilized anti-TCR but exhibit normal survival in vitro (6). Thymocytes from TRAF2.DN or TRAF2-/- mice have enhanced sensitivity to TNF-induced death, consistent with a role for TRAF2 in opposing the apoptotic effects of TNFRs (6, 7).

Several TRAF2-binding members of the TNFR family, including OX40, CD27, and 4-1BB, play an important role in T cell survival and memory responses (13, 14, 15, 16, 17, 18, 19, 20, 21, 22). To determine the overall impact of TRAF2-linked receptors on T cell responses, in this report we have analyzed the role of TRAF2 using MLR as well as influenza infection of TRAF2.DN mice. Overall, TRAF2.DN mice show a dramatic impairment in secondary T cell responses, suggesting an important role for the TRAF2-linked receptors in T cell memory.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice, cell lines, Abs, and reagents

C57BL/6 and BALB/c mice were obtained from Charles River Laboratories (St. Constant, Quebec, Canada) and used at 8–12 wk of age. Heterozygous mice expressing the TRAF2.DN transgene were obtained from Dr. Y. Choi (University of Pennsylvania School of Medicine, Philadelphia, PA) (6). All animal protocols were approved by the University of Toronto animal care committee according to the guidelines of the Canadian Council on Animal Care. Cells were maintained in RPMI 1640 supplemented as previously described (23). Influenza peptide nuclear protein (NP)147–155 was obtained from the Alberta Peptide Institute (Edmonton, Alberta, Canada).

Lymphocyte isolation and MLR

T cells were isolated by both complement and nylon wool depletion of APC and Percoll isolation as described (23). Primary MLR cultures were performed in 24-well plates consisting of 1 x 106 T cells and 1–2 x 106 irradiated (2000 rad) T-depleted APC in a total volume of 1.5 ml. The stimulator population was depleted of T cells by Ab and complement depletion (23). IL-2 was detected using the indicator cell line CTLL as described (9, 24). ELISA was performed on diluted supernatants from the cultures using pairs of anti-murine IFN-{gamma} and anti-murine IL-4 Abs purchased from BD PharMingen (San Diego, CA).

Influenza virus infection

Mice were infected with 200 hemagglutinating units of influenza A HKx31 (H3N2) produced as described (25). At 21 days postinfection, mice were sacrificed and T cells were purified from spleen and restimulated with BALB/c APC plus influenza NP147–155, a dominant H-2Kd-restricted peptide in the CD8 T cell response to influenza virus in BALB/c mice (26). Assay conditions were as described in Ref. 13 . For analysis of CD4 T cell responses in influenza-infected mice, T cells were purified from mice infected 7 days previously with influenza and restimulated in vitro with heat-killed influenza virus plus irradiated splenocytes as APC.

Intracellular IFN-{gamma} staining

Spleen cell suspensions were restimulated in culture medium (RPMI/10% FCS with antibiotics and 2-ME) for 5 h at 37°C with 2 µM influenza peptide NP147–155 peptide (26) and processed for intracellular cytokine staining as described (13).

Cytotoxicity assay

Mice were infected with influenza A HKx31 as above. Splenocytes were harvested after 21 days and 5 x 106 purified T cells were restimulated in vitro by the addition of 1 µM of the H-2Kd-restricted peptide NP147–155 to cultures containing 5 x 106 BALB/c APCs. On day 7, cells were tested for cytolytic activity against 51Cr-labeled P815 cells pulsed with 50 µM NP147–155 peptide in a standard 51Cr release assay as described (13).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
TRAF2.DN mice are defective in allogeneic T cell responses in a MLR

TRAF2.DN mice express TRAF2 245–501 in their lymphoid cells at 20 times the level of endogenous TRAF2 (6). This construct lacks the zinc and RING finger domains of TRAF2 but retains the TRAF domain, 310–501, responsible for binding to the cytoplasmic tails of TNFR family proteins (5). Although dendritic cells and macrophages in these mice should not be affected by the transgene expression, B cells express the TRAF2.DN, so it was important to determine whether APC function was impaired in these mice. To examine the effects of TRAF2.DN expression on T cells vs APC, we conducted MLRs using T cells purified from TRAF2.DN or wild-type (WT) BALB/c (H-2d) mice, stimulated with allogeneic (H-2b) APC from WT mice (Fig. 1GoA). TRAF2.DN mice had a profound defect in IL-2 production, greatly impaired proliferative responses, and decreased IFN-{gamma} levels in the MLR compared with WT mice (Fig. 1GoA and data not shown). Levels of IL-4 in the supernatants were very low in WT and TRAF2.DN mice (data not shown).



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  		FIGURE 1. TRAF2.DN T cells are defective in the MLR at the level of the T cell. A, Left panel, Purified T cells from WT or TRAF2.DN mice were incubated with irradiated APC from C57BL/6 mice. A, Right panel, Purified T cells from C57BL/6 mice were incubated with APC from WT or TRAF2.DN BALB/c mice. Five days later, serial dilutions of supernatants from the cultures were analyzed for IL-2 content using the IL-2-dependent cell line CTLL. Results shown are the average of triplicate wells ± SEM and are representative of four independent experiments. B, Highly purified resting T cells from WT or TRAF2.DN mice were stimulated with plate-bound anti-CD3 or anti-CD3 plus anti-CD28 and proliferation was measured at 48 h. Results shown are from the same experiment shown in A and are representative of three independent experiments.

 
In contrast to the results with TRAF2.DN T cells, T-depleted spleen cells from WT or TRAF2.DN mice showed equivalent ability to induce IL-2 production and proliferation in the MLR (Fig. 1GoA and data not shown). Thus, T cell but not APC function is severely impaired in TRAF2.DN mice. We also analyzed the proliferation of highly purified T cells in response to anti-CD3 plus anti-CD28 (Fig. 1GoB). Under these conditions, we found no defect in T cell proliferation and cytokine secretion to anti-CD3 or anti-CD3 plus anti-CD28. In contrast, Lee et al. (6) had seen a defect in anti-TCR-induced proliferation in these mice. Differences in our studies from previous analysis of TRAF2.DN mice may be due to differences in the purity of the T cells, because in our studies we were particularly careful to eliminate APC in the T cell preparations. Thus, defects in the MLR in TRAF2.DN mice are attributed to a defect in TRAF2-linked signaling pathways rather than some developmental defect or defect in TCR signaling in the T cells.

We also examined B cell proliferative responses. In two of three experiments, B cell proliferation to LPS or CD40L was indistinguishable between WT and TRAF2.DN mice, although in one experiment there was an increased B cell proliferative response to LPS (data not shown). Lee et al. (6) had reported an increase in B cell proliferation to LPS or CD40L, but not to anti-IgM, using T-depleted B cells. The smaller effect on proliferation seen here may reflect differences between using Percoll-isolated resting B cells, vs total T-depleted B cells used by Lee et al. (6), or may be due to differences in mouse strain used (BALB/c in this report vs C57BL/6 in Ref. 6). Nonetheless, it is clear that B cell proliferative responses are unimpaired or slightly enhanced in TRAF2.DN mice.

The secondary Ab response to trinitrophenol-keyhole limpet hemocyanin was also similar between WT and TRAF2.DN mice with respect to IgM, IgG1, and IgG2a production (data not shown). Thus, B cell Ab production and class switch are unimpaired in TRAF2.DN mice. This result differs from the results of Nguyen et al. (12), who showed that Ab responses were defective in TRAF2-/-TNFR1-/- or TRAF2-/-TNF-/- mice. This difference might reflect additional effects of TNF signaling on Ab responses. Thus, B cell and APC function are unimpaired in TRAF2.DN mice.

Defect in secondary T cell responses to influenza virus in TRAF2.DN mice

The above results imply that defects in TRAF2.DN mice are largely limited to T cells rather than APC. This finding allowed us to use the TRAF2.DN mice to test the net effect of blocking all TRAF2-linked members of the TNFR family on T cell responses in vivo. Influenza infection of mice is highly sensitive to costimulation and therefore provides a sensitive measure of the efficacy of the T cell response (13, 15, 17, 27). 4-1BBL-/- mice show no defect in initial CD8 T cell expansion in response to influenza virus but show decreased T cell numbers late in the response and decreased secondary responses (13). Similarly, OX40-/- mice show impaired proliferative responses of CD4 T cells upon restimulation with influenza virus in vitro (27). At day 7 after primary influenza infection, similar numbers of IFN-{gamma}-secreting CD8 T cells were detectable after restimulation of splenocytes from both WT and TRAF2.DN mice (Fig. 2GoA). All the IFN-{gamma}-producing cells were of the CD62Llow phenotype (data not shown). The lack of the defect in primary response in TRAF2.DN mice is consistent with the previous findings that members of the TNFR family primarily influence memory T cell responses. Therefore, we focused our attention on secondary responses to influenza in the mice. TRAF2.DN mice have enlarged spleens due to an abnormal number of B cells. However, the ratio of CD4 to CD8 T cells is unchanged. To avoid anomalies due to differences in overall numbers of splenocytes, for further analysis of T cell function in WT vs TRAF2.DN mice, we purified T cells from the influenza-infected mice and restimulated them with T-depleted splenocytes from WT BALB/c mice. After a 7-day restimulation, the proportion of CD8 cells that secrete IFN-{gamma} in response to NP147–155 peptide was decreased by ~2-fold in TRAF2.DN mice (Fig. 2GoB). Conversion of the data to the percentage of IFN-{gamma}-producing cells per 106 cells recovered reveals a much greater defect in the number of NP147–155-specific responding CD8 T cells, attributed to poorer expansion of CD8 T cells in the TRAF2.DN cultures (Fig. 2GoC). Although influenza-specific secondary responses were clearly decreased in TRAF2.DN mice, all the responding cells were of the CD62Llow phenotype, and we did not observe any difference in the total number of CD62Llow cells in influenza-infected or uninfected WT or TRAF2.DN mice (data not shown). The decreased number of IFN-{gamma}-secreting cells in the secondary response to influenza is unlikely to be due to a lack of ability to secrete IFN-{gamma} by these cells, because there was no defect in the primary IFN-{gamma} secretion in response to influenza virus in these mice (Fig. 2GoA). The secondary CTL response to influenza was also severely impaired in these mice, such that 10- to 30-fold more effector cells were required from TRAF2.DN mice to obtain equivalent killing to that observed with T cells from WT mice (Fig. 2GoD). Thus, there is a correlation between the amount of CTL killing and the number of NP147–155-responsive IFN-{gamma}-producing CD8 T cells in the cultures.



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  		FIGURE 2. TRAF2.DN mice have impaired secondary CD8 and CD4 T cell responses to influenza A virus. WT and TRAF2.DN BALB/c mice were infected i.p. with 200 hemagglutinating units of influenza A virus strain HKx31 and sacrificed at day 7 or 21. A, Splenocytes from mice infected 7 days previously with influenza were restimulated for 6 h with NP147–155 peptide and analyzed for IFN-{gamma} production by flow cytometry. B–D, Equal numbers of purified T cells from day 21-infected mice were restimulated in vitro for 7 days with NP147–155 peptide plus irradiated T-depleted APC from BALB/c mice. B and C, Intracellular cytokine staining. Cells were restimulated with NP147–155 and analyzed for CD8 and IFN-{gamma} staining. Each data point represents a single mouse with average marked with a line, and differences between means for WT and TRAF2.DN are statistically significant (p < 0.01). B, Results are reported as the percentage of CD8 T cells producing IFN-{gamma}. C, Results are reported as number of IFN-{gamma}-producing cells per 106 live cells. D, Cytotoxic (CD8) T cell assay. Cells from the cultures described in A were incubated with 51Cr-labeled P815 cells pulsed with NP147–155 and specific lysis was measured at four E:T ratios. Data are presented as mean ± SEM of four individual mice and are representative of three separate experiments. E, IL-2 production by CD4 T cells was measured by bioassay on CTLL cells after a 48-h stimulation with heat-inactivated influenza virus of T cells from mice infected 7 days previously. The data presented are the average ± SEM of four individual mice and results are representative of three experiments.

 
To examine the role of TRAF2-linked receptors in CD4 T cells during influenza infection, T cells from influenza-infected mice were isolated and restimulated with heat-inactivated virus. Stimulation with heat-inactivated virus results in CD4 but not CD8 T cell activation (28). The T cells from TRAF2.DN mice showed a profound defect in the ability to produce IL-2 in response to secondary exposure to heat-inactivated influenza virus, with the response reduced to background levels (Fig. 2GoE). Similarly, T cell proliferation was also greatly reduced in the TRAF2.DN cultures (data not shown).

In summary, the results presented in this report demonstrate that T cells from TRAF2.DN mice show a profound decrease in T cell responses in both a MLR and in secondary CD4 and CD8 T cell responses to influenza virus. This defect in secondary CTL function in TRAF2.DN mice is much more striking than the defect observed with mice deficient in individual members of the TNFR family. For example, in 4-1BBL-/- mice there is a 3-fold defect in the secondary CTL response to influenza virus (13, 15) compared with the 10- to 30-fold defect observed in TRAF2.DN mice (this report). CD27-/- mice show no defect in CTL effector function but have decreased numbers of influenza-specific CD4 and CD8 memory cells in spleen and lung (17). The dramatic decrease in the MLR in TRAF2.DN mice is to be contrasted with single knockouts in this family also, because 4-1BBL-/- mice show no defect in the MLR or in skin allograft rejection in the presence of an intact CD28 signaling pathway (15).

The TRAF2.DN protein can block the binding of TRAF2 as well as other TRAF proteins to conserved TRAF binding sites on TNFR family members. For example, Wong et al. (11) have provided evidence for competitive effects of the TRAF2.DN and TRAF5.DN in response to TRANCE signaling. Thus, the TRAF2.DN protein serves as a general blocking agent for any of the TNFR family members with a TRAF2 binding site, and likely interferes, e.g., with binding of both TRAF1 and TRAF2 to 4-1BB and TRAF2, TRAF3, and TRAF5 to OX40 (1). In addition, one cannot rule out other indirect or unexpected effects of the TRAF2.DN protein. Nonetheless, the finding that both the CD4 and CD8 secondary response to influenza is dramatically impaired in TRAF2.DN is consistent with a critical role of TRAF-linked receptors in CD4 and CD8 T cell memory.

The observation that TRAF2.DN so dramatically impairs the MLR has implications for transplantation, making TRAF2 an attractive target for drug discovery aimed at blocking conserved TRAF2 binding sites of the TNFR family. These data highlight the importance of TRAF2-linked members of the TNFR family in secondary T cell responses and suggest that several members of the TNFR family may cooperate to provide optimal T cell survival/memory.


   Acknowledgments
 
We thank Yongwon Choi for providing TRAF2.DN mice.


   Footnotes
 
1 This work was supported by a grant from the Canadian Institutes of Health Research and a grant from the National Institute of Canada with funds from the Canadian Cancer Society (to T.H.W). J.L.C. was supported in part by a Canadian Institutes of Health Research doctoral award. Back

2 Current address: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892. Back

3 Address correspondence and reprint requests to Dr. Tania H. Watts, Department of Immunology, University of Toronto, Room 5263 Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail address: tania.watts{at}utoronto.ca Back

4 Abbreviations used in this paper: TRAF, TNFR-associated factor; TRANCE, TNF-related activation-induced cytokine; CD40L, CD40 ligand; JNK, c-Jun N-terminal kinase; NP, nuclear protein; WT, wild type. Back

Received for publication April 16, 2002. Accepted for publication July 29, 2002.


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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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J. Leukoc. Biol., June 1, 2004; 75(6): 962 - 972.
[Abstract] [Full Text] [PDF]

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R. A. Prell, D. E. Evans, C. Thalhofer, T. Shi, C. Funatake, and A. D. Weinberg
OX40-Mediated Memory T Cell Generation Is TNF Receptor-Associated Factor 2 Dependent
J. Immunol., December 1, 2003; 171(11): 5997 - 6005.
[Abstract] [Full Text] [PDF]

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